Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide treatment are lacking. We recently determined the mutational profile of 74 HNSCC, and mutations of genes in the PI3K signaling pathway were detected in nearly one quarter of these cancers. These results were subsequently validated in larger HNSCC cohorts including the HNSCC TCGA. As the PI3K pathway is eminently targeted with multiple drugs that are in early phase clinical development, this provides an immediate opportunity to define predictive biomarkers and implement potentially effective therapeutic approaches for HNSCC. We have developed novel HPV-positive and HPV-negative HNSCC models to identify oncogenic driver mutations in this cancer. In addition, we can assess PI3K pathway mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice as well as tumors from HNSCC patients enrolled on a novel phase II trial of a PI3K pathway inhibitor. This project will therefore elucidate the role of PI3K activation as a biomarker in HNSCC progression, and facilitate the identification of a subset of HNSCC patients where treatment with a PI3K targeting agent represents an effective therapeutic strategy.